Predictive Role of Preoperative Whole-Body 18F-FDG PET/CT for Risk Stratification of Early-Stage (FIGO I-IIA) Cervical Cancer Patients Treated by Surgery

Introduction: The aim of the present study was to investigate the predictive value of maximum standardized uptake value (SUVmax) measured on preoperative 18F-fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography (18F-FDG PET/CT) in International Federation of Gynecology and Obstetrics (FIGO 2009) stage I-IIA cervical cancer patients who were treated with radical hysterectomy. Methods: A total of 47 patients with FIGO stage I-IIA cervical cancer who were evaluated preoperatively with biopsy and 18F-FDG PET/CT followed by radical hysterectomy were included in the study. Correlation between SUVmax and pathological risk factors or survival was studied. Results: The mean SUVmax was significantly higher in patients with large tumor size (≥4 cm), advanced stage (IIA>IB>IA) and depth of invasion >50%. No significant difference was noted in SUVmax between patients with and without pelvic lymph node involvement (P=0.639). SUVmax of the primary tumor with and without lymph-vascular invasion were 12.95 and 10.35, respectively (P=0.5). No significant difference was noted between patients with high SUVmax and low SUVmax with regards to overall survival (OS) and disease-free survival (DFS), using an optimal cut-off value of 7.65 for OS and DFS obtained from receiver operating characteristic (ROC) curve analysis. Patient with tumor size >4cm had 5.9 times more probability of mortality compared to tumor size <4cm (P=0.09). Conclusion: The present study observations showed that although SUVmax is associated with pathological variables, it does not independently predict oncological outcomes in FIGO stage IA-IIA cervical cancer patients who were treated with radical hysterectomy. These findings suggest that SUVmax of primary tumor may be used for risk stratification, but not for prognostication in surgically treated early-stage cervical cancer patients. Not using other parameters of 18F-FDG PET/CT like metabolic tumor volume (MTV), tumor lysis glycolysis (TLG), small sample size, variation in calculation of SUVmax, histopathologic heterogeneity, inclusion of stage IA patients in the study were constraints of present study. Further studies with large sample size using multi metabolic parameters of 18F-FDG PET/CT, including the SUVmax,SUVmean,SUVpeak, MTV and TLG are needed.


Introduction
Carcinoma cervix is one of the most common malignancies in women with an incidence of 16.5% and mortality rate of 7.5% [1].Patients with locally advanced and early-stage cervical cancer were treated by chemoradiotherapy and surgery respectively [2][3][4][5].Approximately one fourth of early stage (International Federation of Gynecology and Obstetrics (FIGO) I to IIA) patients develop recurrence.Pathological factors like size, histological type, lymph-vascular space invasion (LVSI), and lymph node status have been used to assess the risk of recurrence [6][7][8][9].Postoperative radiotherapy with or without chemotherapy was given to patients with high risk of recurrence [3,4,9,10].Selection of patients for adjuvant therapy is important because of its effect on survival and quality of life [4,9].Identification of independent marker that is associated with biological behavior of cervical cancer is needed along with conventional clinicopathological factors for tailoring the treatment and to avoid dual modality treatment, thereby improving the outcomes in early-stage cervical cancer patients.In many cancers, 18 F-fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography ( 18 F-FDG PET/CT) was used for diagnosis, staging and response assessment [11].In patients with ovarian cancer and endometrial cancer maximum standardized uptake value ( SUV max ), measured on 18 F-FDG PET/CT was found to be useful for diagnosis and prognosis [12][13][14][15]. 18F-FDG PET/CT has high clinical impact in management of gynecological cancers as it can alter the management plan [16].The role of 18 F-FDG PET/CT as a staging tool in cervical cancer was confirmed in previous study [17].Though the association between SUV max and pathological features of primary tumor has been studied, its prognostic role was not confirmed [18][19][20][21].There is limited evidence on impact of SUV max in early-stage cervical cancer patients treated by surgery [19,20,22].The present study intends to investigate the predictive role of SUV max measured on preoperative 18 F-FDG PET/CT for risk stratification of earlystage cervical cancer patients treated by surgery.Primary objective of the study was to assess association between SUV max and recurrence rate or disease-free survival (DFS) or overall survival (OS), secondary objective was to assess the association between SUV max and adverse clinicopathological parameters.

Materials And Methods
After approval from the institutional ethics committee (Roc.Operational definitions: 1) Recurrence -Cancer recurrence was defined as when cancer was found in a patient after completion of treatment and a period in remission had passed; 2) DFS -It was defined as the time from end of treatment to recurrence of tumor or death related to cancer; 3) OS -It referred to the total duration of living time from the end of treatment to death due to any other cause.

Statistical analysis
All data was entered into Microsoft excel sheet.Statistical analysis was done by using SPSS software version 2021.Clinicopathological risk factors and the prognostic data were analyzed for association with the SUV max .Cut-off values of the SUV max were determined by the receiver operating characteristic (ROC) curves.Study participants were divided into two groups.Group 0 with SUV max below the cut off value (<7.65) and Group 1 with SUV max above the cut off value (>7.65).Two-sample T test was used to compare the median SUV values in the different subgroups.DFS was calculated using the Kaplan-Meier method.The Cox proportional-hazards model was used for the multivariate analyses.Variables shown to be significant (P<0.05) in the univariate analysis were selected for the Cox model.A P-value of less than 0.05 was considered as significant.

Results
The

Correlation between SUV max and DFS
Correlation between SUV max and DFS is shown in Figure 1.There was no difference in DFS between two groups (Group 0 with SUV max <7.65 and Group 1 with SUV max >7.65).

Correlation between SUV max and OS
Correlation between SUV max and OS is shown in Figure 2.There was no difference in OS between two groups (Group 0 with SUV max <7.65 and Group 1with SUV max >7.65; P=0.23).The difference between the two groups was statistically not significant (p=0.23,Log-rank test).
SUV: Standardized uptake value; OS: Overall survival

Association of tumor size and recurrence
Association between tumor size and recurrence is shown in Table 4. Patients with tumor size >4cm had 2.1 times high probability of recurrence compared to tumor size <4cm, though not statistically significant (P=0.37).

Association between tumor size and mortality
Association between tumor size and mortality is shown in Table 5. Patients with tumor size >4cm had 5.9 times more probability of mortality compared to tumor size <4cm (P=0.09).

Variables
Hazard ratio 95% CI p-value

Discussion
There were conflicting results regarding predictive and prognostic role of SUV max in cervical cancer patients (FIGO stage I-IV) treated by surgery, radiotherapy or palliative treatment [18,19].These different results may be due to treatment bias as disease stages and treatment modalities were different.In early stage (IA-IIA) cervical cancer treated exclusively with surgery, there have been controversial studies on the role of SUV max , Lee et al. showed impaired DFS was correlated with high SUV max , while Crivellaro et al. showed increased recurrence was not associated with SUV max [19,21].To clarify the predictive value of SUV max the present study focused on FIGO stage IA -IIA who were only treated by surgery as primary modality.In present study, there was statistically significant difference between median SUV max and FIGO stages, lower and higher stage tumor had lower and higher SUV max respectively.Present study results are in concordance with study by Chung et al. that reported that higher FIGO stages are associated with high SUV max (P =0.01) [22].In contrast, Yu et al. reported that no statistical significance between groups with stage IB and IIA diseases in relation to SUV max (P > .05)[24].In a study done by Yagi et al., SUV max of the primary tumor on preoperative 18 F-FDG-PET/CT was a prognostic indicator in patients with stage IA2 to IIB cervical cancer treated with radical hysterectomy [25].
Present study showed that a high SUV max of primary tumor was significantly correlated with presence of conventional adverse clinicopathological risk factors such as tumor size, depth of cervical stromal invasion.
In the present study, the median SUV max of tumor <4cm and > 4cm was 9.7 and 13.6, respectively, which was comparable with study done by Xu et al., in which <4cm tumor SUV max was 9.77 and tumor > 4cm the SUV max was 14.86 [26].In present study and study done by Xu et al., there was statistically significant difference between the two groups, which means higher SUV max correlates with large size tumor.In the present study, the median SUV of tumor in patients with cervical stromal depth of invasion>50% was 13, which was comparable with studies done by Xu et al. (12.44) and Zhang et al. [26,27].Further, in these studies and the present study, there was statistically significant difference in SUV max between the two groups.Cut-off values of SUV max for predicting lymph node metastasis was 6.03, cut-off for OS and DFS were 7.36 and 5.59, respectively, in all stages (IA-IIA).Consistent with present results, the study by Yun et al.
showed that the cut off value of SUV max >6 was predictive of DFS in stage IA-IIA [28].In contrast, Lee et al.
The study by Kidd et al. observed three subgroups according to the SUV max cut off values low (<5.2),middle (5.2-13.3),and high (>13.3)[18].Among these studies the cut-off values of SUV max are different it can be due to 18 F-FDG PET/CT settings, image analysis, condition of patient, and stage of disease.
In the present study, we did not find any significant differences in recurrence rate, DFS and OS among the two groups group with SUV max <7.65 and SUV max >7.65.Our findings are in concordance with study done by Crivellaro et al. [21].In contrast, our findings are not in concordance with study done by Lee et al., who reported that in early-stage cervical cancer, tumors with high SUV max (≥13.4) are at increased risk of recurrence [19].
In this study, the hazard ratio for mortality was 5.9 times higher in tumors >4cm compared to tumors <4cm (P=0.09), which is in concordance with study done by Wagner et al. that reported that with inclusion of size >4 cm for stage IIA cancers in new FIGO staging system for cervical cancer, it was better correlated with survival and overall prognosis [29].Also, a study done by Kyung et al. reported that tumor size (4 vs 4-6 cm, P=.0371; and 4 vs >6 cm, P=.0024) was an independent predictive factor for the prognosis of stage II to IV cervical cancer [30].

Limitations
Other parameters of 18

Conclusions
SUV max on preoperative whole body 18 F-FDG PET/CT can be used to differentiate between stage I and II cancer and to predict unfavorable clinicopathological features in FIGO stage IA-IIA patients who have undergone radical hysterectomy.These findings suggest that the SUV max of the primary tumour may be a promising marker for risk stratification in surgically treated, early-stage invasive cervical cancer patients.The present study did not find any difference in long term oncological outcomes between the groups; however, it showed higher hazard of recurrence and mortality in patients with tumor size > 4cm, which in turn correlated with higher SUV max .Future studies with large sample size and inclusion of other 18 F-FDG PET/CT parameters along with SUV max may throw light on their prognostic significance and individualizing treatment in early stage (IA2-IIA2) cervical cancer patients undergoing radical hysterectomy.

FIGURE 1 :
FIGURE 1: DFS in two groups with lower and higher SUVmax (cut-off value 7.65) Figure1: Group 0 indicates SUV max < 7.65 and Group 1 indicates SUV max >7.65.The difference between the two groups was statistically not significant (P=0.3,Log-rank test) SUV: Standardized uptake value; DFS: Disease-free survival

TABLE 1 : Clinicopathological characteristics of study population
FIGO: International Federation of Gynecology and Obstetrics; SCC: Squamous cell carcinoma; AD: Adenocarcinoma; ASD: Adenosquamous Association

between SUV max and clinicopathological parameters
Association between the SUV max and clinicopathological factors is shown in Table2.Significant difference in SUV max was observed among the FIGO stage groups (P= 0.015).The mean SUV max was significantly higher in patients with large tumor size (≥4 cm) compared to patients with tumor size less than 4 cm (P= 0.01).There was no significant difference in SUV max between patient with positive pelvic nodes and negative pelvic nodes (P=0.639).The SUV max of the tumor showing presence and absence of lymph vascular invasion was 12.95 and 10.35, respectively (P=0.5).The median SUV max of tumors with depth of invasion ≥50% was almost thrice that of tumors with depth of invasion <50% (P=0.003).2024 Singaram et al.Cureus 16(1): e53107.DOI 10.7759/cureus.531073 of 9 Risk

between SUV max and recurrence rate
Correlation between SUV max and recurrence rate is shown in Table3.Recurrence rate in patients with SUV max <7.65 and SUV max >7.65 were 8.3% and 17.1%, respectively (P=0.65).

TABLE 3 : Correlation between SUVmax and recurrence rate
SUV: Standardized uptake value some of the limitations observed in our study.Further studies using multi metabolic parameters of18F-FDG PET/CT, including SUV max , SUV mean , SUV peak , MTV, and TLG are needed.
F-FDG PET/CT like metabolic tumor volume (MTV) and tumor lysis glycolysis (TLG) were not used along with SUV max for prognostication in this study.Small sample size, variation in calculation of SUV max , histopathologic heterogeneity, and inclusion of stage IA patients in the study were 2024 Singaram et al.Cureus 16(1): e53107.DOI 10.7759/cureus.53107